Prostate cancer is the second leading cause of cancer death in American males. Although androgen therapy can temporarily control metastatic disease, most tumors become hormone refractory and then rapidly progress since there is no other effective therapy. Thus, there is an urgent need for new therapies. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to epithelial cells. In normal tissues, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. But on tumor cells, PSMA contains a single transmembrane domain and a large extracellular domain. This cell-type specificity makes the large extracellular domain of PSMA an ideal candidate for immunotherapy. We propose development of fully human anti-PSMA monoclonal antibodies for the treatment of prostate cancer. Using Xenomice that are transgenic for the human immunoglobulin gone locus and proven immunization/screening strategies, we will generate a panel of human antibodies that recognize native, cell-surface SMA. Antibodies will be evaluated for specificity and antitumor properties in "naked" form and when conjugated to novel alpha- and beta-emitting therapeutic radionuclides. Furthermore, we will examine antibody efficacy in the best available models of human prostate cancer to identify a lead candidate to advance into human clinical trials. PROPOSED COMMERCIAL APPLICATION: The overall goal of this poposal is to identify the most promising anti-PSMA antibody for treating prostate cancer and advance that therapeutic into clinical testing. The lead antibody construct identified with this proposed research will be moved into clinical trials and, if effective in humans, will be manufactured for commercial sale for the treatment of prostate cancer. The market for a successful immunotherapy includes men at risk for the development of recurrent or metastatic diseases. THis would include a significant fraction of individuals diagnosed with prostate cancer, or 179,000 individuals in the U.S. The ex-U.S. market is approximately equal in magnitutde.